A Novel p53-PP2A Signaling Pathway Is Responsible for Regulation of Hematopoiesis Induced by TGFß.

TGFβ has been reported to play an important role in regulating the proliferation of hematopoietic cells. Dysfunction of signal transduction pathway of TGFβ may result in leukemogenesis. It has been generally accepted that Smads mediate the TGFβ signaling to inhibit cell proliferation, while several Smad4-defective cell lines have been shown to retain certain levels of responsiveness to TGFβ, suggesting an additional TGFβ signaling pathway for cell cycle arrest. We previously demonstrated the evidence for a novel signal pathway for G1 arrest linking TGFβ and p53/Protein phosphatase 2A (PP2A) in CD4+ T lymphocyte and megakaryocytes (ASH, San Diego, 2003). We also showed that, upon TGFβ stimulation, PP2A was transiently recruited by heteromeric complex of TGFβ receptors (TβRs), released into cytosol, and activated. Subsequently, PP2A dephosphorylated p53 to import it into nucleus by interacting with importin-α/β, followed by p21Waf1 induction. In this study, we extended our observation to explore TGFβ-induced growth suppression is required for increment of PP2A activity by using SiRNA against PP2A. When PP2A of CD4+ lymphocytes was knocked-down by specific SiRNA for PP2A, the recruitment of PP2A by TβRs and TGFβ-induced growth suppression as well as nuclear import of p53 were inhibited. As a result, TGFβ stimulation induces PP2A activation and subsequently dephosphorylated-p53 was translocated into nucleus. Thus these results further define a novel pathway of TGFβ-induced growth suppression linking p53-PP2A, and suggest that dysfunction of p53 may result in the escape from growth inhibitory signal of TGFβ in hematological malignancies.